Drug abuse is a significant concern to society in general and especially to those responsible for the nation's public health. The long-term effects and toxicity of most drugs of abuse are not known, especially as they relate to alteration of brain chemistry. Experiments are outlined in this proposal to continue our investiqation of the effects of abused drugs on neurotransmitter levels, and on enzymes responsible for their synthesis. We have previously found that methamphetamine, administered in repeated toxic doses, decreases tyrosine hydroxylase activity in the nigrostriatal and mesolimbic areas of the brain and that antipsychotic agents and GABA transaminase inhibitors prevent the methamphetamine-induced decrease in enzyme activity. Contrary to our previously proposed hypothesis, we have determined that this effect cannot be attributed to inhibition via the striatonigral feedback pathway. Alternative mechanisms for the effect of methamphetamine are suggested and experiments are outlined to test these proposed mechanisms. The effects of other drugs (including phencyclidine, cocaine and ephedrine) will be tested on central dopamine and 5-hydroxytryptamine metabolism and the results will be compared with those observed after methamphetamine administration. The role metabolites of methamphetamine will be investigated and the effects of long-term administration of small daily doses of methamphetamine will be studied. Electron microscopic and neurotransmitter uptake studies are proposed to determine whether neuronal integrity is retained when abused drugs are administered in toxic doses. The proposed studies are designed to generate information concerning the nature of the biochemical lesion(s) which occur in the brain when CNS stiumulant drugs are abused and will help elucidate the interrelationship between dopaminergic, serotonergic and cholinergic neurons. The data and concepts which will evolve from these investigations should also provide information pertinent to a better understanding of parkinsonism and other CNS disorders.